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PanDox: Targeted Doxorubicin in Pancreatic tumours

PanDox Logo

Full Title

Feasibility of Enhanced Chemotherapy Delivery to non-resectable Primary Pancreatic Tumours Using Thermosensitive Liposomal Doxorubicin (ThermoDox®) and Focused Ultrasound

Chief Investigator: Professor Mark Middleton

Sponsor: University of Oxford

Study Design

PanDox is a phase I study to quantify the enhancement in delivery of intratumoural doxorubicin concentration in pancreatic tumours. Drug release is triggered from systemically circulating ThermoDox® by highly localized hyperthermia induced by extracorporeal ultrasound-guided FUS device at sub-ablative powers. Patients are assigned to receive either doxorubicin (Arm A) or ThermoDox® (Arm B).

This window-of-opportunity study takes advantage of the time period that patients wait prior to undergoing first line treatment. We plan to deliver the therapeutic intervention during the period that patients wait to commence first-line treatment for locally advanced or metastatic pancreatic cancer. By utilising this window of opportunity, experimental treatment can occur without disruption to planned standard of care therapy.

Study Population

18 evaluable patients with localised advanced or metastatic pancreatic adenocarcinoma, where surgical resection is not indicated, will be enrolled into the study. All patients will be reviewed for the feasibility of performing FUS and anaesthetic, as assessed by a multi-disciplinary team at the site, for suitability into Arm A (doxorubicin) or Arm B (ThermoDox®) using the following criteria:

  • BMI more than/less than 35?
  • Suitable for general anaesthetic +/- jet ventilation?
  • Tumour visible on US with patient in prone position?
  • Distance from tumour to the stomach, duodenum, colon >1 cm?
  • Any clinical reasons which would prevent ThermoDox being assigned?

Study Schema

Picture shows Schema for the PanDox Study

Study Status

Study Status Recruiting
Target Recruitment Total 18 patients: Arm A (doxorubicin) = 6, Arm B (ThermoDox®) = 12
Participating Site Churchill Hospital, OUH NHS Foundation Trust, Oxford

Inclusion Criteria

  
1.   Able to give informed consent prior to any screening procedures being performed and is able and willing to comply with the protocol and its requirements.


2.   Male or Female, aged 18 years or above.

3.   Prior histological or cytological confirmation of pancreatic adenocarcinoma

  • Non-resectable or metastatic (stage IV)
  • The primary pancreatic lesion measuring at least 1.5cm minimum diameter and amenable to EUS biopsy sampling

4.   ECOG performance status 0-1 

5.   Left ventricular ejection fraction (LVEF) ≥ 50% as determined by echocardiogram

6.   Willing to allow his or her General Practitioner and Consultant, if appropriate, to be notified of participation in the trial.

7.   Life expectancy of at least 3 months

8.   Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use highly effective contraception during the trial and for 6 months thereafter.

9.   Participant has clinically acceptable laboratory results during screening window:

Lab Test

Value required

Haemoglobin (Hb) (transfusion to achieve this allowed)

≥ 9g/dL

Neutrophils

≥ 1.5 109/L

Platelet count

≥ 100 109/L

ALT

≤ 2.5 x ULN

Alkaline phosphatase

≤ 5 x ULN

Serum Bilirubin (stenting to achieve this allowed)

≤ ULN

Creatinine Clearance (Calculated by Cockcroft-Gault criteria)

≥ 50ml/min

INR

<1.5 unless taking oral anticoagulant (this to be stopped at least 1 week prior to biopsy, at which point this INR  limit will then apply)

Exclusion Criteria

  1. Significant renal or hepatic impairment.
  2. Unstable ischemic heart disease, cardiac dysrhythmias, coronary/peripheral artery bypass graft or cerebrovascular accident within 6 months prior to starting treatment
  3. Uncontrolled arterial hypertension despite medical treatment.
  4. Ongoing congestive heart failure or cardiac dysrhythmias of NCI CTCAE Grade ≥2 or uncontrolled atrial fibrillation.
  5. Previous myocardial infarction or acute inflammatory heart disease
  6. On-going significant infection (chest, urine, blood, intra-abdominal).
  7. Uncontrolled diabetes.
  8. Scheduled elective surgery or other procedures requiring general anaesthesia during the trial.
  9. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such procedure
  10. Previous targeted therapies to the pancreatic adenocarcinoma (including radiofrequency ablation or radiotherapy)
  11. History of other malignancy less than 3 years before the diagnosis of current cancer, EXCLUDING the following: Non-melanoma skin cancer, in situ carcinoma of the cervix treated surgically with curative intent, other malignant tumours that have been treated curatively and patient is deemed disease-free
  12. Endocrine therapy - patients with prostate cancer may continue to receive endocrine therapy to maintain castrate levels of androgens
  13. Known hypersensitivity or allergic reactions to any of the drugs or liposomal components or intravenous imaging agents used in this study
  14. Resting ECG with QTc >480msec at 2 or more time points within a 24h period (using Fredericia correction).
  15. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that the investigator considers would make the patient a poor trial candidate, would impart excess risk associated with study participation or drug administration or could interfere with protocol compliance or the interpretation of trial results.
  16. Female participant who is pregnant, lactating or planning pregnancy during the course of the trial. However, those female patients who have a negative serum pregnancy test before enrolment and agree to use one highly effective form of contraception (oral, injected or implanted hormonal contraception or intrauterine device) in addition to condom plus spermicide, for four weeks before entering the trial, during the trial and for six months afterwards are considered eligible.
  17. Male patients with partners of child-bearing potential unless they agree to take measures not to father children by using one form of highly effective contraception including: oral, injected or implanted hormonal contraception or intra-uterine device in addition to condom plus spermicide, during the trial and for six months afterwards). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) during the trial and for six months afterwards to prevent exposure to the foetus or neonate.
  18. Participants who have participated in another research trial involving an investigational product in the past 12 weeks.
  19. Severe immunologic defect or compromised bone marrow function.
  20. Patients who are serologically positive for Hepatitis B, Hepatitis C or HIV.
  21. Previous doxorubicin and epirubicin must not have exceeded 450 mg/m2 and 850 mg/m2, respectively.  
  22. Patients who have a contraindication to MRI scans, for example patients who have a cardiac pacemaker, will be excluded from Arm B (as per Arm Assignment criteria, see ‘Study Population’ criteria above).

Primary Objective

To quantify the enhancement in intratumoural doxorubicin concentration when delivered with ThermoDox® and mild hyperthermia generated non-invasively by focused ultrasound (FUS) compared to free drug alone.

Key Dates

Opened to recruitment: 14th June 2021

Expected closure to recruitment: 29th April 2022